Boronic acid derivatives are widely used in organic synthesis for the formation of carbon-carbon bonds. In Suzuki coupling, an aryl halide and an aryl- or vinyl-borate ester or boronic acid are coupled using Pd(PPh3)4 (N. Miyaura, T. Yanagi and A. Suzuki Synth. Commun. 1981, 11, 513). Aryl triflates are also effective coupling partners (T. Ohe, N. Miyaura and A. Suzuki J. Org. Chem. 1993, 58, 2201).
Boronic acid derivatives have been used during natural product synthesis (P. Rocca et al. Tetrahedron Lett. 1993, 34, 7919), material synthesis (J. P. Sauvage et al. Tetrahedron Lett. 1993, 34, 5125), poly(arylene) polymerization (T. I. Wallow et al. J. Am. Chem. Soc. 1991, 113, 7411) and oligoarene liquid crystals preparation (J. W. Goodby et al. J. Mater. Chem. 1993, 3, 821). One important feature of this kind of chemistry is that boronic acids, in general, are relatively non-toxic and air- and moisture-stable compounds.
Organic aryl, heteroaryl boronic acids and their derivatives can be obtained by different synthetic routes: cross-coupling of bis(pinacolato)diboron (B2pin2) with aryl halides and vinyl halides (Miyaura borylation reaction) or by conversion of aryllithium or arylmagnesium compounds with a boronic acid trialkyl ester followed by acid hydrolysis (T. Leermann, F. R. Leroux, F. Colobert Org. Lett. 2011, 13, 4479-4481).
However, the above described synthetic approaches for the preparation of organic aryl and heteroaryl boronic acids present some limitations, mainly linked to the presence of some functional groups that are not compatible with the employed reaction conditions. For example, the presence of an amino group can interfere with the formation of the organometallic compound. Several synthetic strategies were thus applied for the preparation of aminoaryl- and aminoheteroaryl boronic acids and esters using different amino protective groups.
US patent application 2008/269523A1 describes the possibility to protect bromo aminoaryl and bromo aminoheteroaryl substrates as imino derivatives with benzophenone.
Alternatively, CN102367260A describes the possibility to use t-butyloxycarbonyl derivatives (t-BOC derivatives) of bromo aminoheteroaryl compounds.
Moreover, the amino group can also be protected as N,N-dibenzyl derivative, which is a functional group that can be removed by catalytic hydrogenation (see U.S. Pat. No. 7,196,219B2) or as N,N-trimethylsilyl derivative, which is unstable to moisture (Tetrahedron Lett. 2003, 44(42), 7719-7722).
Unfortunately, the scale-up of these aforementioned synthetic approaches have some important drawbacks, since upon working on the scale of kilograms, it has never been possible to obtain the described overall yields of US2008/269523A1 (i.e. 38-66%), but only considerable lower yields (about 2-10%) in very long reaction times (several days) in order to obtain a conversion higher than 90%.
The main problem connected with the lack of reproducibility of what described in US2008/269523A1 is due to the formation of the imino derivatives; as a matter of fact, the reaction between benzophenone and the aminoaryl or aminoheteroaryl derivative described in Examples 1-10 of the above patent application occurs with very low yields.
Other parameters have been taken into consideration to solve this problem, such as the presence of water, the employed catalyst and the solvent. In particular, the presence of water is known to be critical for the preparation of imino derivatives, since it can influence negatively the equilibrium of the reaction.
The longer reaction times at larger scale can also explain the lower/varying yields because the application of harsh reaction conditions for long periods of time can clearly results in degradation.
Although the reason for this unexpected behavior is not completely clear, it was required to improve the method described in US2008/0269523A1 in order to get to reasonable reaction rate at larger scale (kg or mt) without sacrificing the benefits of the method described.
Lastly, di-tert-butylcarbonate, the protective reagent described in CN102367260A, is known to be very toxic (fatal if inhaled), flammable and unstable to moisture, which makes it particularly unsuitable for industrial use.
It is therefore desirable to provide an improved process for preparing aminoaryl- and aminoheteroaryl boronic acids in high yields on a large scale, which makes use of non-toxic and easy-to-handle reagents.